A Differential Hypofunctionality of Gαi Proteins Occurs in Adolescent Idiopathic Scoliosis and Correlates with the Risk of Disease Progression

Abstract

Adolescent idiopathic scoliosis is the most prevalent spine deformity and the molecular mechanisms underlying its pathophysiology remain poorly understood. We have previously found a differential impairment of melatonin receptor signaling in AIS osteoblasts allowing the classification of patients into three biological endophenotypes or functional groups (FG1, FG2 and FG3). Here, we provide evidence that the defect characterizing each endophenotype lies at the level of Gαi proteins leading to a systemic and generalized differential impairment of Gi-coupled receptor signaling. The three Gαi isoforms exhibited a selective serine phosphorylation patterns for each AIS endophenotype resulting in a differential reduction in Gαi protein activity as determined by cellular dielectric spectroscopy and small interfering RNA methods. We found that one endophenotype (FG2) with phosphorylated Gαi 1 and Gαi 2 was consistently associated with a significantly high risk of spinal deformity progression when compared to the other two endophenotypes (FG1 and FG3). We further demonstrated that each endophenotype is conserved among affected family members. This study expands our understanding of the mechanism underlying the Gi-coupled receptor signaling dysfunction occurring in AIS and provides the first evidence for its hereditary nature. Collectively, our findings offers a new perspective on Gαi hypofunctionality in a human disease by revealing specific serine phosphorylation signatures of Gαi isoforms that may facilitate the identification of AIS patients at risk of spinal deformity progression.

Patient outcomes in idiopathic scoliosis are associated with biological endophenotypes: 2020 SOSORT award winner

“…In this study, we are proposing the first hypothesis relating brace outcome and intrinsic cellular profile connected to the roles of GPCRs as mechanosensors. This study evaluated patient outcomes based on three biological endophenotypes defined by the differential hypofunctionality of Gi alpha subunits [10,11] as initially evidenced by a differential dysfunction of melatonin signal transduction [7][8][9]. Differences between the three endophenotypes acquired through a cell-based assay were identified in the outcomes of brace treatment both for final Cobb and progression criteria.…”

“…In complex multifactorial disorders, such as AIS, biological endophenotypes have the potential utility both in identifying risk genes and in enlightening the pathophysiology. We previously identified three distinct biological endophenotypes for AIS based on a differential protein G inhibitory (Gi) signaling dysfunction in AIS patients [7][8][9][10][11]. These observations led to the classification of patients into three biological endophenotypes or "functional groups" (referred to as FG1, FG2, and FG3), based on the maximal Gi response observed after Gi alpha subunits stimulation [11].…”

“…We previously identified three distinct biological endophenotypes for AIS based on a differential protein G inhibitory (Gi) signaling dysfunction in AIS patients [7][8][9][10][11]. These observations led to the classification of patients into three biological endophenotypes or "functional groups" (referred to as FG1, FG2, and FG3), based on the maximal Gi response observed after Gi alpha subunits stimulation [11]. This molecular classification is very specific given the differential hypofunctionality of the three Gi alpha subunits occurring in each AIS endophenotype while such patterns are not observed among healthy controls [11].…”

“…These observations led to the classification of patients into three biological endophenotypes or "functional groups" (referred to as FG1, FG2, and FG3), based on the maximal Gi response observed after Gi alpha subunits stimulation [11]. This molecular classification is very specific given the differential hypofunctionality of the three Gi alpha subunits occurring in each AIS endophenotype while such patterns are not observed among healthy controls [11]. With respect to AIS development and its nonsurgical treatments (e.g., bracing), the importance of biomechanics [12,13] and bodily responses to mechanical stimuli [14] is generally well established and holds many possibilities for novel personalized therapeutic options.…”

“…Nevertheless, the mechanisms by which biomechanical cues may affect cellular functions or bracing response, as well as how the sensing apparatus and transduction of mechanical signals operate in AIS pathogenesis, remain poorly understood. Among the known components of the mechanotransduction pathway, G protein-coupled receptors (GPCR) [15] and more specifically Gi-coupled receptor signaling attracted our attention given our previous findings [11]. The objective of this study was to determine if distinctive biological endophenotypes among AIS patients could be associated with a differential outcome at maturity.…”